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Venetoclax enhances FLT3-ITD inhibition in AML
BCL-2, BCL-X and MCL-1 promote survival of L
FLT3-ITD+ cells in vivo
In order to understand the role of BCL-XL and MCL-1 in
FLT3-ITD mediated survival in vivo, we utilized selective inhibitors to pharmacologically assess the contributions of the anti-apoptotic proteins. Drug combinations of quizar- tinib, venetoclax, navitoclax (dual BCL-2/BCL-XL inhibitor)8 and AMG 176 (MCL-1 inhibitor)11 were tested in the MV4;11 model at well-tolerated and clinically rele-
vant doses. AMG 176 dosed at 10 mg/kg achieved a C of ~2 mM in peripheral blood of NSG mice (Online Supplementary Figure S2), which is within the cumulative weekly dose range recently reported11 and 100 mg/kg dose of navitoclax overlaps with clinically achievable exposure.8,9 Other than quizartinib, single agents targeting the anti-apoptotic proteins showed minimal improvement in survival compared to vehicle control while all combina- tions with quizartinib enhanced its single agent activity.
max
A
Figure 6. FLT3-ITD signaling regu- lates the expression of BCL-XL and MCL-1 in vitro. Fms-like tyrosine kinase 3 wild-type (FLT3-WT) (HL60 and OCI-AML3) and FLT3 internal tandem duplication (FLT3-ITD+) (MV4;11 and Molm13) cell lines treated for 24 hours with indicated concentration of quizartinib and cell lysates analyzed by western blot for (A) FLT3-ITD downstream effector proteins and (B) BCL-2 family pro- teins as indicated. (C) Cell lines were treated with 10 nM quizartinib for indicated time and MCL-1 expression was assessed in whole cell lysate by western blot.
B
C
haematologica | 2021; 106(4)
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